NL9000299A - NEW CYCLOSPORIN-CONTAINING GALENIC PREPARATIONS. - Google Patents

Description

Reg.No. 132536 / ThU / MM

New cyclosporin-containing galenic preparations

The present invention relates to new galenic preparations containing a cyclosporine as an active ingredient.

Cyclosporins comprise a class of structurally distinct, cyclic, poly-N-methylated en-decapeptides, which usually have pharmacological, in particular immunosuppressive, anti-inflammatory and / or anti-parasitic activity. The first isolated cyclosporine was the naturally occurring fungal metabolite Ciclosporin or Cyclosporine, also known as cyclosporine A and commercially available under the registered trademark SANDIMMUN® or SANDIMMUNE®. Ciclosporin is the cyclosporin of the formula 1, wherein -MeBmt- represents the N-methyl- (4R) -4-but-2E-en-1-yl-4-methyl- (L) threo-nyl radical of the formula 2, where -xy- represents -CH = CH- (trans).

As the class's parent compound, Ciclosporin has received the most attention so far. Ciclosporin has been studied primarily as an immunosuppressive agent, mainly in connection with its administration to recipients in organ transplants, especially heart, lung, combined heart-lung, liver, kidney, pancreas, bone marrow, skin and cornea transplants, and in particular allogeneic organ transplants. In this area, Ciclosporin has achieved remarkable success and reputation.

At the same time, the use of Ciclosporin in various autoimmune diseases and inflammatory conditions, in particular inflammatory conditions with an etiology, which includes an autoimmune component, such as arthritis (e.g. rheumatoid arthritis, chronic arthritis progress and arthritis deformans) and rheumatic diseases is intensive. and reports and results in vitro, in animal models and in clinical studies are widespread in the literature. Certain autoimmune diseases for which Ciclosporin therapy has been proposed or applied include autoimmune haematologic disturbance (including, for example, haemolytic anemia, aplastic anemia, pure red blood cell anemia and ideopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, sclerodoma, sclerodoma. chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic thrush, autoimmune inflammatory bowel disease (including, for example, ulcerative colitis and Crohn's disease) endocrine ophthalmopathy, Graves' disease, sarcoidosis, multiple sclerosis, primary billiary cirrhosis, 3uvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, for example including idiopathic nephrotic syndrome or n ephropathy with minimal change).

Further areas of research have been potential utility as an antiparasitic agent, in particular against protozoa, with potential use suggested in the treatment of malaria, coccidiomycosis and schistosomiasis and, even more recently, use in cancer therapy, for example as a means of reducing or eliminating of resistance to other antineoplastic or cytostatic therapy.

Since the original discovery of Ciclo-sporin, a wide variety of naturally occurring cyclosporins have been isolated and identified, and many other non-naturally occurring cyclosporins have been prepared by total synthesis or semisynthesis or by the use of modified culture techniques. Thus, the class formed by the cyclosporins is now substantial and includes, for example, the naturally occurring cyclosporins A through Z [c.f. Traber et al. 1, Helv. Chim. Acta. 60, 1247-1255 (1977), Traber et al. 2, Helv. Chim. Acta. 65 No. 162, 1655-1667 (1982), Kobel et al., Europ. J. Applied Microbiology and Biotechnology 14., 273-2740 (1982) and von Wartburg et a., Progress in Allergy, 38, 28-45 (1986)] as well as various non-naturally occurring cyclosporin derivatives and artificial or synthetic cyclosporins, including the so-called dihydro-cyclosporines [in which the -xy- residue of the -MeBmt- residue (formula 2 above) is saturated to yield -xy- = -CH2-CH2-] derivatized cyclosporins (into which, for example, a further substituent has been introduced to the α-carbon of the sarcosyl residue at the 3-position of the cyclosporin molecule), cyclosporins, in which the MeBmt residue is present in isomeric form (in which, for example, the configuration at positions 6 'and 7' of the -MeBmt residue is cis rather than trans) and cyclosporins, which include variant amino acids at specific locations within the peptide series, using the total synthesis method for the preparation of cyclosporins developed by R. Wenger - see e.g. Traber 1, Tra ber 2 and Kobel loc. cit., U.S. Pat. Nos. 4,108,985, 4,210,581, and 4,220,641, European Patent Publications 0 034,567, 0,056,782, and 0,296,122, International Patent Publication WO 86/02080, Wenger 1, Transp. Proc. 15, Suppl. 1: 2230 (1983), Wenger 2, Angew. Chem. Int. Ed., 24, 77 (1985), and Wenger 3, Progress in the Chemistry of

Organic Natural Products. 50, 123 (1986).

Thus, the classes encompassed by the cyclosporins now now include, for example, [Thr] 2-, [Val] 2-, [Nva] 2- and [Nva] 2- [Nva] 5-Ciclosporin (also known as cyclosporine C, D, G, respectively and M) [31-O-acyl-MeBmt] 1-Ciclosporin (also known as cyclosporin A acetate), dihydro-MeBmt] 1- [Val] 2-Ciclosporin (also known as dihydro-cyclosporine D), 3'-deoxy -3 '-oxo-MeBmt] 1 [Val] 2 - and [Nva] 2-Ciclosporin, [(D) -fluoromethyl-Sar] 3-Ciclosporin, [(D) Ser] 8-Ciclosporin, [Melle] 11- Ciclosporin, [(D) MeVal] 11-Ciclosporin (also known as cyclosporine H), [MeAla] 6-Ciclosporin [(D) Pro] -Ciclosporin etc.

[Due to new conventional nomenclature for cyclosporins, these are defined by the structure of cyclosporin (namely cyclosporine A). This is done by first indicating the amino acid residues different from those contained in Ciclosporin (eg "[(D) Pro] 3" to indicate that the cyclosporin in question is a - (D) Pro- instead of having a -Sar- residue in the 3-position) and then applying the term "Ciclosporin" to characterize residual residues identical to those present in Ciclosporin. Individual residues are numbered, starting with the residue -MeBmt-, -dihydro-MeBmt- or its equivalent in position 1]. Very many of these other cyclosporins exhibit comparable pharmaceutical utility or more specific utility with Ciclosporin, for example, in particular, reducing activity on tumor resistance to cytostatic therapy, and proposals for the use of these compounds as therapeutic agents are abundant in the literature.

Despite the very important contribution, that

Ciclosporin has delivered, in particular in the field of organ transplantation and the therapy of autoimmune diseases, its difficulties in giving more active and manageable administration agents, as well as the reported occurrence of undesired side reactions, in particular nephrotoxic reaction, are evident have been serious impediments to wider use or application. The cyclosporins are typically highly hydrophobic. Proposed liquid preparations, for example for oral administration of cyclosporins, have hitherto been primarily based on the use of ethanol and oils or similar excipients as carrier media. Thus, the commercially available Ciclosporin drink contains ethanol and olive oil as the carrier medium in combination with labrafil as the surfactant. - see, e.g., U.S. Patent No. 4,388,307. However, use of the beverage and similar preparations as proposed in the art is accompanied by a series of difficulties.

First, the necessary use of oils or oil-based carriers can give the preparations an unpleasant taste or otherwise reduce palatability, especially in long-term therapy. These effects can be masked by offering in gelatin capsule form. However, in order to keep the cyclosporin in solution, the ethanol content must be kept high. Evaporation of the ethanol, for example from capsules or other forms, when opened for example, leads to the development of a cyclosporine precipitate. When such preparations are presented in, for example, soft gelatin encapsulated form, this particular difficulty necessitates packaging the encapsulated product in an airtight container, for example, between two airtight layers or in a package of two layers of aluminum foil. This in turn makes the product both bulky and expensive to manufacture. As already stated, the properties of the preparations in storage are far from ideal.

The degree of bioavailability achieved using existing oral cyclosporin dosing systems is also small and shows wide variation between individuals, individual patient types, and even in a single individual at different times during therapy. Thus, literature references indicate that currently available therapy using the commercially available Ciclosporin drink provides an average absolute bioavailability of only about 30% with marked variation between individual groups, for example, between liver transplant recipients (relatively low bioavailability) and bone marrow transplantation ( relatively high bioavailability). The reported variation in bioavailability between patients ranges from something between one or a few percent for some patients to as much as 90% or more for others. As already noted, remarkable change in bioavailability for individuals is often observed over time.

In order to obtain effective immunosuppressive therapy, blood or blood serum cyclosporin levels should be maintained within a specified range. The required pathway, in turn, may vary depending on the condition being treated, for example, whether therapy is given to prevent transplant rejection or to fight an autoimmune disease and whether or not other immunosuppressive therapy is being used concomitantly with cyclosporin therapy. . Due to the wide variation in bioavailability achieved with conventional dosage forms, the daily doses required to achieve required blood levels also vary considerably from individual to individual and even in a single individual. For this reason, it is necessary to monitor blood and blood serum levels of patients receiving cyclosporin therapy regularly and frequently. Monitoring of blood / blood serum levels, which is generally done by RIA or equivalent immunoassay technique, for example using monoclone antibody based technology, should be performed on a regular basis. This is inevitably time consuming and inconvenient and contributes significantly to the overall cost of therapy.

In addition to all these very obvious practical difficulties, there is also the occurrence of undesirable side reactions, which have already been alluded to, which have been observed when using available oral dosage forms.

Various proposals have been made in the art for accommodating such problems, including both solid and liquid oral dosage forms. Japanese Patent Application 71682/1985 proposes to use means for increasing the lymphatic release of cyclosporins, especially by administration in combination with surfactants. A general list of surfactants which can be used includes saccharose fatty acid esters, such as sucrose oleate, palmitate or stearate, as well as other fatty acid esters, especially sorbitan fatty acid esters, such as sorbitan oleate, palmitate or stearate. Although use of both mono- and polyesters is indicated, a general preference for mono- or diesters is suggested. Other surfactants listed are polyoxyethylated hydrogenated vegetable oils, such as the known products, which are commercially available under the brands Cremophore RH and Nikkol HCO 60 and are clearly preferred above, for example, the said sucrose surfactants.

Example 3 of this Japanese application describes an aqueous preparation containing an F160 designated saccarose fatty acid ester as a surfactant component. The preparation contains 3.5 mg Ciclosporin and 2 mg saccarose ester in 1 ml H20. To obtain dispersion of the Ciclosporin, 5 min sonication at 100W is required. The resulting preparation, described as a "transparent solution", is used directly in animal models to investigate relative lymphatic resorption. Given the very low solubility of Ciclosporin in H 2 O and the minor amount of surfactant used, it is evident that the alleged solution is an art product of sonication treatment. Not only is the Ciclosporin concentration achieved unsuitably low, but for an oral dosage form, for example, the formulation is unstable by itself and thus de facto excluded as a practical or commercial galenic form of any kind. It is essentially an experimental system, with which one can do laboratory research and no more. There is no proposal for the use of surfactants in any other context except for lymphatic release.

Japanese Patent Application 193129/1987 (Publication No. 038029/1989) describes powder formulations containing a cyclosporin dispersed in a solid, non-surfactant, carrier phase, which includes, for example, sucrose, sorbitol, tartaric acid, urea, cellulose acetate phthalate, methacrylic acid / methyl methacrylate hydroxypropylmethylcellulose phthalate includes, in addition to minor amounts of surfactant. Again, the surfactant is added to enhance the lymphatic release, and in this connection, the application is clearly aimed at providing an intended practical agent for applying the teachings of the above Japanese Application 71682/1985. Reference to sucrose esters as possible surfactant components is omitted in this case. Reference to sorbitan esters as part of a list of possible surfactant components has been retained. However, products of the Nikkol HCO 60 type are again preferably referred to as a surfactant, and Nikkol HCO 60 is the only surfactant used in the examples. There is no indication that the alleged increase in lymphatic release provides any practical benefit or addresses any of the difficulties encountered in the art in cyclosporin therapy as discussed above, for example.

In accordance with the present invention, novel galenic cyclosporin compositions are provided containing fatty acid saccharide monoesters as primary carrier components which mitigate or substantially reduce the difficulties in cyclosporin, e.g., cyclosporin therapy, which have hitherto arisen in the art. In particular, it has been found that the compositions of the invention allow the preparation of solid, semisolid and liquid compositions containing a cyclosporin at a sufficiently high concentration to allow, for example, good oral administration while simultaneously achieving an improved effect, e.g. regarding the bioavailability.

More specifically, it has been found that formulations of the invention allow effective cyclosporin dosing with accompanying increased resorption / bioavailability, as well as reduced variation in resorption / bioavailability, which occurs in both individual patients receiving cyclosporin therapy and between individuals. By applying the teachings of the present invention, one can obtain cyclosporin dosage forms which give less variation in attainable cyclosporin blood / blood serum levels between doses for individual patients as well as between individuals / individual patient groups. Thus, the invention allows reduction of dose levels of cyclosporin required to achieve effective therapy. In addition, it allows more precise standardization as well as optimization of ongoing daily dosage requirements for individual patients receiving cyclosporin therapy as well as for patient groups undergoing equivalent therapy.

By more accurate standardization of the individual patient dosing amount and blood / blood serum level response, as well as dosing and response parameters for patient groups, the requirements for following these magnitudes can be reduced, thus significantly reducing the cost of therapy.

By reducing the required cyclosporin dosage / standardization of bioavailability obtained, the present invention also provides an agent which allows reduction of undesirable side effects occurring, especially nephrotoxic response in patients undergoing cyclosporin therapy.

In addition, the present invention allows for the preparation of non-alkanol based compositions which are, for example, free or substantially free of ethanol. In such preparations, the difficulties discussed above, related to stability and associated preparation inherent in known alkanolic preparations, are avoided. Thus, the invention provides, inter alia, compositions which are more suitable for presentation in a capsule, for example, hard or soft gelatin capsule form and / or present substantially less or no difficulties in packaging as discussed above, for example, in connection with soft gelatin encapsulated forms.

More particularly, the present invention provides: a pharmaceutical composition comprising a) a cyclosporine as an active ingredient, b) a fatty acid saccharide monoester and c) a diluent or carrier, wherein I) component (c) is a solvent for both components ( a) and (b), wherein components (a) and (b) each independently have a room temperature solubility in component (c) of at least 10%, or II) component (c) is a solvent for both components (a) and (b) and components (a) and (c) are present in the composition in a ratio of 1: 0.5 to 50 parts by weight of [(a) :( c)], or III) component (c) a solvent is for both components (a) and (b) and the preparation is formulated in solid dosage unit form suitable for oral administration, or IV) component (c) comprises a poly (C2.4 olefin) glycol having an average molecular weight of at least ten at most 7000 or a viscosity at 50 ° C of at most 15000 mPa.s, whether it contains a c3.5 alkylene polyol ether or ester or V) the preparation does not contain, or is substantially non-aqueous, or VI) component (c) comprises a solid polymeric carrier, an organosilicon polymer or paraffinic per- or sub-liquids and component (a) is present in the preparation in solid solution in (b) .

The preparations defined herein are new and particularly advantageous variants of the preparations, for which rights are generally claimed in French patent application 8811953 and the corresponding applications in countries all over the world, including US patent application 07/243577, German Aus -legeschrift 38 304945, Japanese Patent Application No. 231396/88 and British Patent Application No. 88 21443.9 (first published in France, March 17, 1989 under No. 2,620,336).

The above definitions (I) - (VI) should not be interpreted as mutually exclusive. The compositions of the invention comprise the compositions as defined in accordance with one or more of the defined limitations (I) - (VI). Thus, preferred compositions of the invention satisfy any two or more of (I) - (V).

The term "pharmaceutical preparation" as used herein is to be understood as a definition of preparations, the individual components or components of which are per se pharmaceutically acceptable, ie, when oral administration is intended, acceptable for oral use, or, when external administration is intended, topical are acceptable.

The preferred cyclosporine as component (a) is Ciclosporin. Another preferred component (a) is [Nvas] 2-Ciclosporin, also known as cyclosporin G.

Preferred components (b) for use in the compositions of the invention are water-soluble fatty acid saccharide monoesters, for example fatty acid monoesters of saccharides with a solubility in water of at least 3.3% at ambient temperature, ie, which are water soluble in ambient amount at ambient temperature. at least 1 g of monoester per 30 ml of water.

The fatty acid residue of components (b) can include saturated or unsaturated fatty acids or mixtures thereof.

Particularly suitable components (b) are C6.18 fatty acid saccharide esters, in particular water-soluble C6_18 fatty acid saccharide esters. Particularly suitable components (b) are saccharide monoesters of caproic acid (C6), capry Izmir (C8), capric acid (C ^ g) / lauric acid (* -12) 1 myristic acid (C ^), palmitic acid (C16), oleic acid (C18) / ricinoleic acid (C18) and 12-hydroxystearic acid (C18), especially lauric saccharide monoesters.

The saccharide residue of component (b) can include any suitable sugar residue, for example a mono-, di- or trisaccharide residue. The saccharide residue may well comprise a di- or trisaccharide residue. Preferred components (b) are q fatty acid disaccharide monoesters and C8.18 fatty acid trisaccharide monoesters.

Particularly suitable saccharide residues are sucrose and raffinose residues. Thus, particularly suitable components (b) are: sucrose monocaproate, sucrose monolaurate, sucrose monomyristate, sucrose monooleate, sucrose monoricinolate, raffinose monocaproate, raffinose monolaurate, raffinose monomyristate, raffinose monopalmitate and raffinose monoleate. Most preferred components (b) are raffmos monolaurate and, especially, sucrose monolaurate.

Components (b) may well have a hydrophilic lipophilic balance (HLB) of at least 10. Components (b) may well have an ester residual purity of at least 80%, more preferably at least 90%, most preferably at least 95%. Components (b) may well have a melting point of from about 15 to about 60 ° C, more preferably from about 25 to about 50 ° C.

The above definitions (II) and (III) for the compositions of the invention define components (c) as substances, in which both components (a) and (b) exhibit considerable solubility at prevailing temperature, for example at temperatures of ca. 20 ° C. Preferred components (c) are substances in which (a) and (b) independently have a solubility of at least 10% [as required by definition (I)], preferably at least 25%, most preferably at least 50% (in which, for example, components ( a) and (b) independently have an insolubility of the order of at least 100 mg, preferably 250 mg, most preferably at least 500 mg / ml) at ambient temperature. Particular preference is given to substances in which component (a) has a solubility of at least 10%, preferably at least 25%, most preferably at least 50% and / or in which component (b) has a solubility of at least 100%, more preferably at least 200%, most preferably at least 300% (wherein, for example, component (b) has a solubility of the order of at least 1000, more preferably 2000, most preferably at least 3000 mg / ml).

Components (c) suitable for use in the compositions of the invention are: c1) ethanol, c2) C2-4 alkylene glycols, c3) C3.5 alkylene polyols, c4) poly (C2.4 alkylene) glycols and c5) C3-5 alkylene polyethers or esters as well as all kinds of esters thereof.

However, according to the general objectives of the invention, the use of ethanol either alone or mixed with another component (c) is generally less preferred.

When component (c) is a C2.4 alkylene glycol (c2), it is preferably a propylene glycol, most preferably 1,2-propylene glycol. When component (c) is a C3.5 alkylene polyol (c3), it is preferably a C3-5 alkylene triol, most preferably glycerol.

If component (c) is a poly (C2-4 alkylene) glycol (C4), it may well be a polyethylene glycol. For use in the compositions of the invention, such components preferably have an average molecular weight of no more than 7000 [according to definition (IV)], e.g. up to 6600, more preferably no more than about 2,000, e.g. up to 1600, most preferably no more than about 500. Preferably, such components have a viscosity of at most about 15000 mPa.s, more preferably at most about 1000 mPa.s, most preferably at most about 200 mPa.s at 50 ° C, or better at ambient temperature [conforming to definition (IV )]. Suitable polyethylene glycols for use as components (c) are as described, for example, in Fiedler, Lexikon der Hilfstoffe, 2nd. revised and expanded edition, [1981] vol. 2, on pages 726-731, in particular the products PEG (polyethylene glycol) 200, 300, 400 and 600, as well as PEG 1000, 2000, 4000 and 6000, but especially 200, 300 and 400, which, for example, meet approximately following physical properties; PEG 200 PEG 300 PEG 400 PEG 600 mol. Wt. approx. 190-210 approx. 285-215 approx. 380-420 approx. 570-630 viscosity mPa.s. approx. 46-53 approx. 66- 74 approx. 85-95 approx. 130-150 freezing point approx. -50 ° C approx. -16 to approx. -3 to approx. 15 to

12 ° C 8 ° C 15 ° C

^ 25 approx.1.459 approx.1.463 approx.1.465 approx.1.4 67

When component (c) is a C3.5 alkylene polyol ether or ester (c5), it may well be a C3-5 alkylene triol, especially a glycerol ether or ester. Suitable components (c5) are mixed ethers or esters, ie components, which contain other ether or ester components, for example, transesterification products of C3.5 alkylene triol esters with other mono-, di- or polyols.

Particularly suitable components (c5) are mixed C3-5 alkylene triol / poly (C2.4 alkylene) glycol fatty acid esters, especially mixed glycerol / polyethylene or polypropylene glycol fatty acid esters.

Particularly suitable components (c5) for use in the present invention are products obtained by transesterification of glycerides, e.g. triglycerides, with poly (C 2-4 alkylene) glycols, e.g. polyethylene glycols and, optionally, glycerol. Such transesterification products are generally obtained by alcoholysis of glycerides, for example, triglycerides, in the presence of a poly (C2-4) glycol, for example, polyethylene glycol and, optionally, glycerol (ie, to obtain transesterification of the glyceride component to the polyalkylene glycol / glycerol component, ie, via polyalcohol kylene glycolysis / glycerolysis). Generally, such a reaction is carried out by reacting the indicated components (glyceride, polyalkylene glycol and optionally glycerol) at elevated temperature in an inert atmosphere with continuous stirring.

Preferred glycerides are fatty acid triglycerides, for example (C10-22 fatty acid) triglycerides, including natural and hydrogenated oils, especially vegetable oils. Suitable vegetable oils are, for example, olive oil, almond oil, peanut oil, coconut oil, palm oil, soybean oil and wheat germ oil and in particular natural or hydrogenated oils, which are rich in (C 12-16 fatty acid) ester residues.

Preferred polyalkylene glycol materials are polyethylene glycols, especially polyethylene glycols of molecular weight from about 500 to about 4000, for example from about 1000 to about 2000.

Thus, suitable components (c5) are mixtures of C3-5 alkylene triol esters, for example mono-, di- and triesters in varying proportions and poly (C2-4 alkylene) glycol mono and diesters, together with minor amounts of free C3-5 alkylylene triol and free poly (C2.5 alkyl). leen) glycol. As set forth above, the alkylene triol moiety is preferably glyceryl, preferred polyalkylene glycol moieties are polyethylene glycyl, especially having a molecular weight of from about 500 to about 4000, and preferred fatty acid moieties are C 1 to 3 fatty acid moieties , especially saturated C10.22 fatty acid ester residues.

Thus, particularly suitable components (c5) may optionally be defined as: transesterification products of a natural or hydrogenated vegetable oil and a polyethylene glycol and optionally glycerol, or preparations comprising or consisting of glyceryl mono-, di- and tri-C10_22 fatty acid esters and polyethylene glycyl mono and di-C10 22 fatty acid esters (optionally in addition, e.g., under appropriate amounts of free glycerol and free polyethylene glycol).

Vegetable oils, polyethylene glycols or polyethylene glycol residues and fatty acid residues, which are preferred in connection with the above definitions are set forth above. Particularly suitable components (c5) as described above for use in the present invention are known and commercially available under the trademark Gelucir, in particular the products:

I) Gelucir 33/01, which has a melting point = approx. 33-38 ° C

and a saponification number = 240/260, II) Gelucir 35/10, mp = approx. 29-34 ° C, saponification number = approx. 120-140, III) Gellucir 37/02, mp. = Approx. 34-40 ° C, saponification number = approx. 200-220, IV) Gellucir 42/12, mp. = Approx. 41-46 ° C, saponification number = approx. 95-115 ° C, V) Gelucir 44/14, mp. = Approx. 42-46 ° C, saponification number = approx. 75-95, VI) Gelucir 46/07, mp. = Approx. 47-52 ° C, saponification number = approx. 125-145, VII) Gelucir 48/09, mp. = approx. 47-52 ° C, saponification number = approx. 105-125, VIII) Gelucir 50/02, mp. = Approx. 48-52 ° C, saponification number = 180-200, IX) -Gelucir 50/13, mp. = .46-41 ° C, saponification number = approx. 65-85, X) Gelucir 53/10, mp. = Approx. 48-53 ° C, saponification number = approx. 95-115 ° C, XI) Gelucir 62/05, mp = approx. 60-65 ° C, saponification number = approx. 70-90.

The above products (I) - (X) all have an acid number = <2. Product (XI) has an acid number = <5. The above products (II), (III) and (VI) - (X) all have an iodine value = <3. Product (i) has an iodine number = ^ 8.

Products (IV) and (V) have an iodine value = <5. Product (XI) has an iodine value = <10. Components (c5) with an iodine number = <1 are generally preferred. Of course, mixtures of components (c5) as defined in the compositions of the invention can also be used.

As a component (c) as described in particular above [i.e. a component that complies with any of the above definitions (I) - (IV) or a component as defined under (c1) - (c5)] is used, the compositions of the invention generally comprise component (a) in a carrier medium, which comprises components (b) and (c). Usually components (a) and (b) are each present in the compositions of the invention in dispersion or solution, for example, a molecular miscelle dispersion or solution (including, if applicable, solid solution). Thus, component (a) is generally present in dispersion or solution in both components (b) and (c) and component (b) in turn is present in solution in (c). Component (b) generally acts as a carrier or solubilizing agent (or before and / or after administration) for component (a) in the compositions of the invention, and component (c) acts as a carrier or fluidizing agent. (Of course, the present invention should not be construed as in any way limited to any particular functional relationship between components (a), (b) and (c), unless otherwise stated).

Furthermore, when component (c) is used as above, it is further preferred that the compositions of the invention be formulated in a solid dosage unit form suitable for oral administration, for example, presented in hard or soft gelatin encapsulated form, suitable for oral administration [according to definition (III)]. Such dosage unit forms can, as described in more detail, well contain, for example, 2-200 mg of component (a) per dosage unit.

When using a component (c) as mentioned above, components (a) and (c) are preferably present in the compositions of the invention in a ratio of 1: 0.5-50 parts by weight [(a) :( c )] [in accordance with definition (II)]. Components (a) and (b) may well be present in a ratio of 1: 3 to 200 parts by weight [(aj. (B)].

When using a component (c) as mentioned above, it is further preferred that the compositions of the invention are not aqueous or substantially non-aqueous [according to definition (V)], for example with a water content of less than 20%, more preferably less than 10%, more preferably less than 5%, 2% or 1%, based on the total weight of the preparation.

According to the above, the present invention also provides in a series of preferred embodiments.

- a pharmaceutical composition comprising a component (a) and a component (b) as defined above and a diluent selected from one of the components (c1) - (c4) as defined above, or any mixture thereof and satisfying one of the above definitions (II) - (V), - a pharmaceutical preparation comprising a component (a), (b) and (c2) as defined above and meeting the above definitions (II), (III) or (V) and - a pharmaceutical composition comprising a component (a), (b) and (c5) as defined above.

If one specifically describes a component (c) as above [i.e. a component that complies with any of the definitions (I) - (IV) or any of the components (c1) - (c5)] used in the compositions of the invention may contain components (a) and (c) in these compositions well present in a ratio of about 1: 0.5 to 50 parts by weight. Better, components (a) and (c) are present in a ratio of about 1: 1 to 10, more preferably from 1: 1 to 5, most preferably from about 1: 1.5 to 2.5, e.g. about 1: 1.6 or 1: 2 parts by weight [(a): (c)]. Components (a) and (b) may well be present in these compositions in a ratio of about 1: 3 to 200, preferably about 1: 3 to 100, more preferably about 1: 3 to 50 parts by weight. Better, components (a) and (b) are present in a ratio of about 1: 5 to 20, preferably from about 1: 5 to 10, most preferably from about 1: 6.0 to 6.5, for example about 1: 6 25 parts by weight [(a) :( b)].

When the components of the invention contain saccharose monolaurate as component (b) and 1,2-propylene glycol as component (c), components (a) and (b) are preferably present in a ratio of about 1.6 to 7 parts by weight [(a): (b)] and components (a) and (b) are preferably present in a ratio of about 1: 1.5 to 2.5, for example about 1: 2 parts by weight [(a): (b)].

Compositions of the present invention containing a component (b) as above may be formulated into any suitable dosage form for, for example, oral, parenteral or topical administration, for example, for dermal or ophthalmic administration, for example, for administration to the ocular surface, for example, for the treatment of autoimmune disorders of the eye, as set forth above, or for intralesional injection, for example, in the treatment of psoriasis.

Such preparations can be readily brought into unit dosage form, whether or not for oral administration.

The amount of component (a) present in such dosage unit forms naturally varies with, for example, the condition to be treated, the intended mode of administration and the desired effect. Generally, however, such dosage unit forms may well contain from about 2 to about 200 mg of component (a), for example, Ciclosporin per dosage unit.

Suitable dosage forms for oral administration are, for example, liquids, granules and the like. Preferably, however, solid dosage units are, for example, tableted or encapsulated forms, especially in hard or soft gelatin encapsulated forms. Such oral dosage unit forms may well contain about 5 to about 200 mg, more preferably about 10 or 20 to about 100 mg, e.g. 15, 20, 25, 50, 75 or 100 mg of component (a), e.g. Ciclosporin, per dosage unit.

Compositions according to the present invention, which comprise a component (c) as mentioned above, have the further advantage that they can provide the basis for preparations with modified release properties, for example delayed release of component (a) or release of component (a) during for a long time, for example after oral administration. Such compositions additionally comprise (d), a component, which can modify the release properties of the composition with respect to component (a). Such components (d) are, for example, polymeric excipients, in particular thickeners, for example polymeric or colloidal thickeners, as well as agents that are water-swellable, for example water-swellable polymers or colloids.

Suitable components (d) are known in the art and include: d1) polyacrylate and polyacrylate copolymer resins, for example, polyacrylic acid and polyacrylic acid-methacrylic acid resins, as known and commercially available under the trademark Carbopol (cf Fiedler, loc. Cit., 1 pp. 206-207), in particular the products Carbopol 934, 940 and 941, and Eudragit (cf Fiedler, loc. cit., 1, pp. 372-373), in particular ?? the products Eudragit E, L, S, Rl, and RS and especially the products Eudragit E, L and S.

d2) Cellulose and cellulose derivatives, including: alkyl celluloses, for example methyl, ethyl and propyl celluloses, hydroxyalkyl celluloses, for example hydroxypropyl celluloses, and hydroxypropylalkyl celluloses, such as hydroxypropylmethyl celluloses, hydroxyethyl cellulose acetates, cellulose acetates, cellulose acetates, cellulose acetates, cellulose acetates, cellulose acetates, cellulose acetates, cellulose acetates, such as sodium, carboxymethyl celluloses. Examples of such products suitable for use in the present invention are known and commercially available, for example, under the trademarks Klucel and Methocel (cf Fiedler, loc. Cit., 1, p. 521 and 2, p. 601), in particular the products Klucel LF, MF, Gf and HF and Methocel K 100, K 15M, K 100M, E 5M, E 15, E 15M and E 100M.

d3) Polyvinylpyrrolidones, including, for example, poly-N-vinylpyrrolidones and vinylpyrrolidone copolymers, such as vinylpyrrolidone-vinyl acetate copolymers. Examples of such compounds suitable for use in the present invention are known and commercially available under the brand Kollidon (cf Fiedler, loc. Cit., 1, p. 526 and 527), in particular the products Kollidon 30 and 90.

d4) Polyvinyl resins, including, for example, polyvinyl acetates and polyvinyl alcohols, as well as other polymers, including gum tragacanth, gum arabic, alginates, e.g. alginic acid, and salts thereof, e.g. sodium alginates.

d5) silicon oxides, including hydrophilic silicon dioxide products, for example, alkylated (e.g., methylated) silica gels, especially colloidal silica products as known and commercially available under the trade name Aerosil [c.f. Handbook of Pharmaceutical Excipients, published by the Pharmaceutical Society of Great Britain, pp. 253-256], in particular Aerosil 130, 200, 300, 380, 0, OX 50, TT 600, MOX 80, MOX 170, LK products 84 and the methylated Aerosil R972.

If a component (d) is present, it may well be present in an amount of about 0.5-50 wt%, more preferably about 1-20 wt%, most preferably about 2-10 wt%, by weight on the total weight of components (a) + (b) + (c) + (d).

As component (c) in the compositions of the invention includes: (c ^) a solid polymeric carrier as required by the above definition (VI), this is preferably a water-insoluble, or substantially water-insoluble polymeric carrier.

Particularly preferred as components (c) are pyrrolidones [c.f. Fiedler, loc. cit., 2. pp. 748-750] including, especially cross-linked polyvinylpyrrolidones. Examples of such materials suitable for use in the present invention are known and commercially available under the trademark Kollidon [c.f. Fiedler, loc. cit., 1, p. 527], Kollisept [c.f. Fiedler, loc. cit., 2, pp. 719-720], Povidone and Crospovidone [c.f. Fiedler, loc. cit., 2, p. 751].

Especially suitable components (c6) are polyvinyl pyrrolidones with a molecular weight of at least about 10,000, more preferably at least about 20,000 or 25,000, for example, with a molecular weight of about 40,000 or more. Cross-linked polyvinylpyrrolidones are of particular interest. Examples of products suitable for use in the present invention as (c) are in particular: Plasdone XL, Plasdone XL 10 and Crospovidone.

When the compositions of the invention comprise a component (c6), they preferably also include (d) a water-swellable or water-soluble component, for example, a cellulose or cellulose derivative as defined under (d2) above.

Other examples of such substances of particular interest in connection with the compositions of the invention are a component (c6) as known and commercially available under the trademarks Avicel [c.f. Fiedler, loc. cit., 1, pp. 160-161], Elcema [c.f. Fiedler, loc. cit., 1, p. 326] and Pharmacoat [cf Fiedler, loc. cit., 2 / p. 707], for example the products Avicel PH 101 and PH 102, Elcema and Pharmacoat 603.

In case the compositions of the invention comprise a component (c6), component (a) in component (b) is present in solid solution, including solid micellar solution, for example wholly or substantially wholly in molecular or micellar dispersion, [show in practice components (b) have at least some fluidity, for example at prevailing or slightly elevated temperature, and are therefore not "solid" in the strictest sense. The term "solid solution" as used herein is to be interpreted accordingly and includes, for example, viscous or highly viscous systems. ]. The solid solution formed by (a) and (b) can be well dispersed, for example in finely divided form, i.e. by component (c6). Thus, components (c6) in compositions of the invention generally serve as a disintegratable matrix for [(a) + (b)]. Components (d) generally serve as aids in disintegration, for example in contact with the contents of the gastrointestinal tract.

Compositions of the invention, which include a component (c6), may also include good (e), a binder and / or lubricant. Substances suitable for use as a binder / lubricant are in particular fatty acid and alkyl sulfonic acid salts, for example metal salts with, for example, 10 or more carbon atoms in the fatty acid / alkyl radical, for example, alkali and alkaline earth salts of C10-22 fatty acids and C10-22 alkyl sulfonic acids, e.g. sodium , calcium or magnesium salts. Examples of such materials suitable for use in the present invention are: sodium lauryl sulfate and magnesium stearate [c.f. Fiedler, loc. cit., 2., p. 584].

When compositions of the invention contain a component (c6), components (a) and (b) may well be present in a ratio of about 1: 2 to 20, preferably about 1: 2.5 to 10, most preferably about 1: 3 to 8 [(a): (b)].

Components (c6) may well be present in compositions of the invention in an amount of at least 10 wt%, more preferably at least 15 wt%, even more preferably at least 20 wt%, based on the total weight of the composition. Suitable components (c6) are present in compositions of the invention in an amount of 10-60 wt%, more preferably 15-50 wt%, e.g. about 20-40 wt%, e.g. about 25.30 or 35 wt .%, based on the total weight of the preparation.

If a component (d) is present, components (d) and (c6) may well be present in a ratio of about 1: 0.5 to 4. more preferably from about 1: 1 to 3, most preferably from about 1: 1.5 to 2.5, for example about 1: 2 or about 1: 2.5 parts by weight. [(d): (c6)].

If a component (e) is present, components (e) and (c6) may well be present in a ratio of from about 1: 5 to 25, preferably from about 1: 5 to 20, preferably from about 1 : 7 to 15 parts by weight [(e) :( c6)].

When the compositions of the invention comprise all three components (c6), (d) and (e), they may well be present together in an amount of about 25-75 s, more preferably about 30-65%, most preferably 40 -65%, based on the total weight of the preparation. The ratio of components [(a) + (b)]: [(c) + (d) + (e)] may well be in the order of 1: 0.25 to 7.5, more preferably 1: 0, 5 to 5, preferably from 1: 0.5 to 2, preferably about 1: 0.8, 1: 1.2 or 1: 1.3 parts by weight.

Compositions of the invention comprising a component (c6) can be prepared in any suitable dosage form for, for example, oral, parenteral or topical administration. Such preparations according to the invention can be prepared well in dosage unit form, whether or not for oral administration.

The amount of component (a) present in such dosage unit forms naturally varies depending on, for example, the condition to be treated, the intended mode of administration and the desired effect. In general, however, they may well contain from about 2 to about 200 mg of component (a), for example Ciclosporin, per dosage unit.

Suitable dosage forms for oral administration are granules and the like. However, preference is given to solid dosage unit forms, for example tableted or encapsulated forms. Such oral dosage unit forms may well contain from about 5 to about 200 mg, more preferably from about 10 or 20 to about 100 mg, for example 15, 20, 25, 50, 75 or 100 mg of component (a), for example Ciclosporin, per dosage unit.

As component (c) in the compositions of the invention includes: (c7) an organopolysiloxane oxide or paraffin per- or sub-liquid as required by the above definition (VI), component (c7) is preferably readily liquid at temperatures up to 150 ° C , preferably up to 100 ° C, more preferably up to 50 ° C. Components (c7) may well have a maximum viscosity of 15,000 mPa.s, more preferably 1000 mPa.s, at the indicated temperatures.

Paraffin hydrocarbons suitable for use as component (c7) are liquid and semisolid paraffins and mixtures thereof, i.e. paraffinum subliquidum and paraffinum perliquidum [see Fiedler loc. cit., 2, pp. 690-691]. In order to permit easy processing, component (c7) may well consist wholly or substantially of liquid or semi-solid paraffins, i.e. paraffinum perliquidum or paraffinum subliquidum or mixtures thereof. However, if it is desired to produce compositions having, for example, slower active ingredient release properties, this can be accomplished by further addition of a solid paraffin, i.e., paraffinum durum.

When compositions of the invention contain liquid or solid paraffins only as component (c7), they are preferably present in a ratio of about 1: 0.5 to 1.0 [liquid: semi-solid]. In this case, components (a) and (c7) may well be present in a ratio of from about 1: 6 to 200, more preferably from about 1: 6 to 100, most preferably from about 1: 6 to 20, e.g. about 1 : 8 parts by weight [(a) :( c)].

Moreover, when compositions according to the invention comprise a solid paraffin as component (c7), the ratio of liquid / semi-solid paraffin: solid paraffin components may well be about 1: 0.06 to 0.1 parts by weight. In this case, components (a) and (c7) may well be present in a ratio of 1: 6 to 200, more preferably from 1: 6 to 100, most preferably from 1: 8 to 20, e.g. about 1:10 parts by weight [(a) :( c7)].

Organosilicon oxide polymers suitable for use as component (c7) include, in particular, liquid, ie liquid and semisolid, polymers having a structural unit of the formula ~ R2Si-O- wherein each R2 is a monovalent organic radical, e.g. C1-4alkyl, in particular methyl, or phenyl. Particular preference is given to organosiloxane polymers with a viscosity of about 0.65 to 105 cP, in particular about 10 or 50 to 500 or 1000 CP.

For ease of processing, component (c7) may include good liquid organosiloxane polymers, for example, polymethylsiloxane polymers, for example, a variety of known silicone oils, such as silicone oil 550, DC 200, SF-1066 and SF-1091 [c.f.

Fiedler, loc. cit., 2, p. 826]. When compositions of the invention comprise only liquid organosiloxane polymers, components (a) and (c7) may well be present in a ratio of from about 1: 6 to 200, more preferably from about 1: 6 to 100, most preferably from 1: 6 to 20, for example about 1: 8 parts by weight [(a): (c7)].

For example, compositions having, for example, active ingredient slower release properties, may be obtained using semisolid organosiloxane polymers, for example, a variety of known silicone pastes, for example, silicone paste A [c.f. Fiedler, loc. cit., 2 p. 826] as component (c7) or by adding these, for example, to other organosilicon oxide polymers as described above. In the latter case, the ratio of liquid: semisolid organosiloxane polymers present in the composition of the invention may well be in the order of about 1: 0.5 to 1. In this case, the ratio of components (a) : (c7) are well on the order of about 1: 6 to 100, preferably about 1: 6 to 20 parts by weight [(a) :( c7)].

It is of course also possible to use mixtures of components (c7) as defined in the compositions of the invention.

When compositions of the invention comprise a component (c7), components (a) and (b) may well be present in a ratio of from about 1: 6 to 20, preferably from about 1: 6 to 10, most preferably from about 1: 6.0 to 6.5, for example about 1: 6.25 parts by weight of [(a) :( b)].

In the case of compositions of the invention containing a component (c7), component (a) in component (b) is wholly or substantially present in molecular or micellar dispersion, for example in the form of a solid solution, or a solid micellar solution [wherein the term "solid solution" is used herein in the same sense as in connection with preparations containing a component (c6)]. The solid solution formed by (a) and (b) may well be dispersed in divided, e.g. finely divided, form in component (c7), e.g. through component (c7).

Compositions according to the invention containing a component (c7) can be prepared in any suitable dosage form for, for example, oral, parenteral or topical administration, for example for dermal or ophthalmic administration, for example for administration on the ocular surface, for example for the treatment of autoimmune disorders of the eye, as set forth above, or for intralesional injection, for example, in the treatment of psoriasis. They can be well prepared in dosage unit form, whether or not for oral administration.

The amount of component (a) present in such dosage unit forms naturally varies depending on, for example, the condition to be treated, the intended mode of administration and the desired effect. In general, however, they may well contain from about 2 to about 200 mg of component (a), for example Ciclosporin per dosage unit.

Suitable dosage forms for oral administration are liquids, granules, etc. Preferred, however, are solid dosage unit forms, for example tableted or encapsulated forms, especially in hard or soft gelatin encapsulated forms. Suitable oral dosage unit forms may well be from about 5 to about 200 mg, more preferably from about 10 or 20 to about 100 mg, for example, 15.20, 25, 50, 75 or 100 mg of component (a), for example

Contain cyclosporin, per dosage unit.

Compositions according to the invention, which comprise a component (c7), have the further advantage that they can provide the basis for preparations with modified release properties, for example delayed release of component (a) or release of component (a) for a long time. for example after oral administration. Such preparations can be obtained as described above by the incorporation of solid or semi-solid components (c7) in appropriate amounts. Optionally, they can be obtained by including an additional component (d): a component, which can modify the release properties of the composition with respect to component (a). Such components (d) are, for example, polymeric excipients, in particular thickeners, for example polymeric or colloidal thickeners, as well as substances that are swellable in water, for example water-swellable polymers or colloids, for example all kinds of substances defined under (d1) - (d5) upstairs.

If a component (d) is present it may well be present in an amount of about 0.5-30%, more preferably from about 1 to 20%, most preferably from about 1 to 10%, based on the total weight of components (a) + (b) + (c7) + (d).

Components (d5) are especially indicated for use in compositions of the invention containing an organosilicon oxide polymer as component (c).

Compositions of the invention comprising a component (c6) or (c7) are, or are preferably, non-aqueous or substantially non-aqueous, for example as described above in connection with compositions comprising other components (c).

Compositions of the present invention, regardless of the selected component (c) [for example, when component (c) includes any of the components (c1) - (c7) set forth above or comprises a mixture thereof] may include any additional additives, for example as known and commonly used in the art, for example antioxidants [e.g. ascorbyl palmitate, tocopherols, butylhydroxyanisole (BHA) or butylhydroxytoluene (BHT)], flavorings etc.

In particular, the compositions of the invention may well comprise one or more stabilizers or buffering agents, particularly to prevent hydrolysis of component (b) or degradation of component (a) during processing or storage. Such stabilizers can include acidic stabilizers such as citric acid, acetic acid, tartaric acid or fumaric acid, as well as basic stabilizers such as potassium hydrogen phosphate, glycine, lycin, arginine or tris (hydroxymethyl) aminomethane.

Such stabilizers or buffering agents may be suitably added in an amount sufficient to maintain a pH within the range of from about 3 to about 8, more preferably from about 5 to 7, for example, between 6 and 7. Such stabilizers are generally present in an amount of up to 5% by weight, based on the total weight of the preparation or up to 10% by weight, for example when using citric acid or acetic acid. Compositions according to the invention, in particular preparations, in which component (a) is Ciclosporin, with a pH within the ranges indicated above, are preferred.

Compositions of the invention may also well contain a polyoxyalkylene-free surfactant, for example, dioctyl succinate, dioctyl sulfosuccinate, di [2-ethylhexyl] succinate, sodium lauryl sulfate, or phospholipids, for example lecithin. If a surfactant as mentioned above is present, it may well be present in an amount of 5-50%, more preferably 10-50-6, e.g. 10-25%, based on the weight of component (b).

In case compositions of the invention contain component (a) in solid solution in component (b), for example if component (c) has a component (c6) or (c7) as set out above, any stabilizers, buffers and / or incorporate surfactants as mentioned above into the solid solution phase. Such substances can also be included in component (c), etc.

Regardless of the selected component (c), compositions of the invention are preferably free, or substantially free, of ethanol and contain, for example, less than 5.0%, more preferably less than 2.5%, for example 0-1.0% ethanol, based on the total weight of the preparation.

In addition to the above, the present invention also provides a method of preparing a pharmaceutical composition as defined above, wherein components (a), (b) and (c) are as defined above, optionally together with a component (d) and / or other component, for example stabilizer, buffer or surfactant as described above, intimately mixing or processing and, if required, converting the resulting preparation into a dosage unit form, for example a dosage unit form for oral administration, for example by tabletting, filling in gelatin capsules or other suitable methods.

If component (c) is a solvent for components (a) and (b) or includes a component (c), (c), (c) / (c4) or (c5) as defined above, one can use components (a) , (b) and (c) in the above process well together by dissolving components (a) and (b) together in component (c), for example under heating at temperatures up to 50 ° or 150 ° C, preferably not above 70 or 75 ° C. The mixture thus obtained can then be further processed with components (d), etc., for example by intimate mixing according to methods known in the art. Filling into hard or soft gelatin capsules can be performed well at an elevated temperature, for example up to 50 ° C, in order to keep the preparation liquid, for example in the heat.

In case preparations according to the invention contain component (a) in solid solution in component (b), for example preparations comprising a component (c6) or (c7) as explained above, in this method it is well possible to first prepare a solid solution of ( a) and (b), followed by intimate mixing or processing of the obtained solid solution with the remaining components (c) and optionally (d), etc.

Solid solutions containing components (a) in (b) may be prepared by methods known in the art, e.g. by solidification of a melt containing (a) in solution in (b) or removal of the solvent from a solution of components (a) and (b). For the purposes of the present invention, the latter alternative is generally preferred.

Suitable solvents for components (a) and (b) are lower alkanols, for example ethanol. Stabilizers, buffers and / or surfactants can be well incorporated in the dissolution stage.

The solid solution thus obtained is then suitably processed, for example in finely divided form, with component (c) and optionally components (d) and (e), etc., for example by dispersion in component (c).

Although ethanol can be used to prepare the compositions of the invention, for example to prepare solid solutions as described above, it is preferably removed, for example, by evaporation, before completing the final dosage form to obtain an ethanol-free or substantially ethanol-free product as explained above.

The following examples illustrate the invention.

The product sucrose monolaurate L-1969 used in the examples is commercially available from Mitsubishi-Kasei Food Corp., Tokyo 104, Japan: HLB value = at least 12.3, lauryl ester residual purity = at least 95%, mp. = approx. 35 ° C, decomposition at approx. 235 ° C, surface tension of 0.1% by weight solution in water = approx. 72.0 dyn / cm at 25 ° C.

Examples

Component Relative amount (mg) I. a) Cyclosporine (e.g. Ciclosporin) 50.0 b) Saccharose monolaurate L-1695 312.5 c) 1,2-Propylene glycol 100.0

Total 462.5 II. a) Cyclosporine (e.g., Cyclosporin) 50.0 b) Saccharose monolaurate L-1695 312.5 c) Glycerol 100.0

Total 462.5 III. a) Cyclosporine (e.g. Ciclosporin) 50.0 b) Saccharose monolaurate L-1695 312.5 c) PEG 200 100.0

Total 462.5 IV. a) Cyclosporine (e.g., Cyclosporin) 50.0 b) Saccharose monolaurate L-1695 312.5 c) PEG 400 100.0

Total 462.5 V. a) Cyclosporine (e.g. Ciclosporin) 50.0 b) Saccharose monolaurate L-1695 350.0 c) 1,2-Propylene glycol 100.0 d) Eudragit E 50.0

Total 550.0 VI. a) Cyclosporine (e.g. Ciclosporin) 50.0 b) Saccharose monolaurate L-1695 350.0 c) 1,2-Propylene glycol 100.0 d) Methocel K100 110.0

Total 610.0 VII. a) Cyclosporine (e.g., Cyclosporin) 50.0 b) Saccharose monolaurate L-1695 350.0 c) 1,2-propylene glycol 100.0 d) Aerosil 200 15.0

Total 515.0 VIII. a) Cyclosporine (e.g. Cyclosporin) 50.0 b) Saccharose monolaurate L-1695 350.0 C) PEG 400 200.0 d) Eudragit L 2.5

Total 602.5 IX. a) Cyclosporine (eg Ciclosporin) 50.0 b) Saccharose monolaurate L-1695 312.5 c) Gelucir (eg Gelucir 42/12, 44/14

Or 35/10 100.0

Total 462.5 X. a) Cyclosporine (e.g., Ciclosporin) 50.0 b) Saccharose monolaurate L-1695 312.5 c) Gelucir 100.0 d) Klucel LF 50.0

Total 512.5

The preparation of Example I is prepared by dissolving components (a) and (b) in component (c) with stirring and heating on an oil bath at 100 ° C. The preparations of Examples II-X are prepared in an analogous manner. In the case of Examples V and VIII, component (d) is dissolved in the initially obtained mixture of components (a) - (c). In the case of Examples VI, VII and X, component (d) is suspended in (a) - (c).

The resulting preparations are filled under heating in hard gelatin capsules, size 1 (examples I-IV and IX) or size 0 (examples V-VII and X), to obtain an encapsulated final product, each capsule containing 50 mg of cyclosporine (e.g. Ciclosporin) and is suitable for administration to prevent transplant rejection or to treat autoimmune diseases, for example, by administering 1-5 capsules daily.

Examples

Component Relative amount (mg) XI. a) cyclosporine (e.g. ciclosporin) 100.0 b) saccharose monolaurate L-1695 300.0 c) Plasdone XL 350.0 d) Avicel PH 1023 150.0 e) sodium lauryl sulfate 25.0

Total 925.0 XII. a) Cyclosporine (e.g. Ciclosporin) 50.0 b1) Saccharose monolaurate L-1695 350.0 b2) Saccharose monostearate 50.0 c) Crospovidone 250.0 d) Elceina 150.0 e) Magnesium stearate 30.0

Total 980.0 XIII. a) Cyclosporine (e.g. Cyclosporin) 50.0 b) Saccharose monolaurate L-1695 160.0 c) Plasdone XL 10 200.0 d1) Pharmacoate 603 25.0 d2) Avicel PH 101 75.0 e) Magnesium stearate 20.0

Total 605.0

The above preparations XI-XIII may well each contain 25 mg (f) tartaric acid and / or 50 mg (g) dioctyl succinate, both of which preferably give a final weight for preparation XI of 1000 mg, for preparation XII of 1055 mg and for preparation XIII of 60 180 mg.

Preparations XI-XIII are prepared as follows: Components (a) and (b) are dissolved in absolute ethanol and the ethanol is evaporated under reduced pressure at 50 ° C. Components (c) - (e) are mixed thoroughly [with the addition of (f) and (g) if used] using known mixing methods. The solid solution containing [(a) + (b)] is ground to a fine powder and mixed evenly in [(c) - (g)] and the resulting uniform mass is pressed into tablets, each 100, 50 or 25 mg (a) and are suitable for graft rejection administration or in the treatment of autoimmune diseases, for example, by administration of 1 to 5 tablets daily.

Examples

Component Relative amount (mg) XIV. a) Cyclosporine (eg Ciclosporin) 50.0 b) Saccharose monolaurate L-1695 312.5 c) Paraffinum perliquidum 397.5

Total 760.0 XV. a) Cyclosporine (eg Ciclosporin) 50.0 b) Saccharose monolaurate L-1695 312.5 c) Polysiloxane oil DC200 397.5

Total 760.0

Components (a) and (b) are dissolved in absolute ethanol and the ethanol is evaporated exhaustively at 50 ° C under reduced pressure. The resulting solid solution is ground to a fine powder and suspended uniformly in component (c). The resulting liquid suspension is filled into size 0 hard gelatin capsules to provide an encapsulated final product, each capsule containing 50 mg of cyclosporine (e.g. cyclosporin) suitable for administration to prevent transplant rejection or to treat autoimmune diseases, for example, by administering 1-5 capsules daily.

Examples

Component Relative amount (mg) XVI. a) Cyclosporine (e.g., Cyclosporin) 50.0 b) Saccharose monolaurate L-1695 312.5 c) Paraffinum subliquidum 372.5 d) Paraffinum durum 25.0

Total 760.0 XVII. a) Cyclosporine (e.g., Cyclosporin) 50.0 b) Saccharose monolaurate L-1695 312.5 c) Paraffinum perliquidum 397.5 d) Aerosil 10.0

Total 770.0

Compositions 1XVI and XVII are prepared analogously as XIV and 1XV above. In the case of preparation XVI, (c) and (d) are first combined by melting and stirring intimately. The solid solution, comprising [(a) + (b)], is then suspended in [(c) + (d)]. In the case of preparation XVII, (d) is suspended together with [(a) + (b)] in (c).

Equivalent preparations such as those of Examples I-XVII can be prepared above using any other cyclosporin, for example [Nva] 2-Ciclosporin instead of Ciclosporin as component (a), or using any other fatty acid saccharide ester, for example as set forth above, for example raffinose monolaurate, instead of saccharose monolaurate as component (b), always in the same or equivalent amount or relative ratio.

The usefulness of preparations according to the invention can be demonstrated by animal or clinical tests, which are carried out, for example, as follows:

Bioavailability test of preparations according to the invention in the dog a) Test preparations

Preparation I (from Example I)

Preparation II (of Example XIV) b) Test Method

Groups of 8 dogs (beagles) (males, approx. 11-13 kg) are used. The animals do not receive feed within 18 hours of administration of test preparation, but have free access to water until administration. The test preparations are administered with the throat probe, followed by 20 ml of NaCl 0.9% solution. The animals are given free access to food and water 3 hours after administration of the test preparation.

Blood samples of 2 ml (or 5 ml for the blank) are taken from the saphenous vein and collected in 5 ml plastic tubes containing EDTA at -15 min (blank), 30 min and 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours after administration. Pending the examination, the blood samples are stored at -18 ° C.

The blood samples are analyzed with RIA. The areas under the drug concentration in the blood versus time curve are calculated according to the trapezoidal rule. Variation analysis is performed with respect to GOK (area under curve), Cmax (maximum concentration) and Tmax (maximum time).

c) Results

The calculated mean GOK (in ng h / ml1) and Cmax (in ng / ml'1) values of typical runs are shown in the following table, along with calculated variation in response between test animals receiving the same preparation (BV).

Preparation COK BV (%) Cmax CV% (0-24 hours) I 3058 19.9 583 30.9 II 2894 14.91 544 19.7

As shown in the table above, compositions of the invention exhibit high bioavailability (GOK and Cmax) coupled with relatively small variation in patient response for both GOK and Cmax.

Similar advantageous results can be obtained using other preparations according to the present Examples I-XVII, in particular the preparations of Examples I-X.

Clinical trial

The beneficial properties of the compositions of the invention when administered orally can also be demonstrated in clinical trials conducted, for example, as follows.

The trial patients are adult volunteers, for example, professionally trained male individuals aged 30-55 years. The test groups may well include 12 patients.

The following included / excluded criteria are used:

Included: normal ECG screen, normal blood pressure and pulse, body weight = 50-95 kg.

Excluded: clinically significantly troublesome medical condition, which could interfere with drug absorption, spread, metabolism, excretion or safety; symptoms of a significant clinical disease in the pre-trial two-week period; clinically relevant abnormal laboratory values or electrocardiogram; need for medical guidance throughout the course of the study; administration of any drug known to have well-defined potential toxicity to a major organ system within the previous 3 months; administration of any trial drug within 6 weeks before entering the trial, history of drug or alcohol abuse, loss of 500 ml or more of blood in the last 3 months, adverse drug response or hypersensitivity; history of allergy, which requires drug therapy; Hep.-B / HIV positive.

A complete physical examination and ECG are performed before and after the test. The following parameters are assessed within a period of 1 month before and after the test:

Blood: - red blood cell count, hemoglubin, hematocrit, erythrocyte sedimentation, white blood cell count, smear, platelet count and glucose fasting,

Serum / plasma - total protein and electrophoresis, cholesterol, triglycerides, Na +, K +, Fe ++, Ca ++, G1, creatinine, urea, uric acid, SGOT, SGTP, -GT, alkaline phosphatase, total bilirubin, α-amylase.

Urinary pH, microalbumin, glucose, erythrocytes, ketone bodies, sediment.

Creatinine brightness is also determined 1 month before entering the trial.

Patients receive test preparations in random order.

Compositions are administered orally, 1 time up to a total dose of 150 mg of cyclosporine, for example Ciclosporin, and are allowed at least 14 days between each administration.

Administration is in the morning after an overnight fast of 10 hours with only water allowed. Only decaffeinated drinks are allowed within the 24-hour period after administration. Patients should not smoke within 12 hours of administration. Patients receive a standard lunch 4 hours after administration.

Blood samples (2 ml) are taken 1 hour before administration and after administration after 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6 , 9, 12, 14, 24, 28 and 32 hours. To determine creatine, 2 ml of blood samples are taken immediately before administration and 12, 24 and 48 hours after administration. Samples for cyclosporin determination are collected in 2 EDTA-coated polystyrene tubes (1 ml each) at each time which are frozen at -20 ° C after gentle stirring. Whole blood cyclosporin is determined using RIA with specific and / or nonspecific MAE test limit in both cases = approximately 10 ng / ml.

In tests conducted according to the above procedure, for example, comparing the preparation of Example I in hard gelatin encapsulated form with the existing Ciclosporin oral solution (Ciclosporin = 50 mg, Labrafil = 150 mg, ethanol = 50 mg, corn oil = 213 mg , in soft gelatin encapsulated form: final weight content = 463 mg / dose) as standard, significantly increased measures of bioavailability for the preparation of Example I are recorded compared to the standard, as reflected in both GOK (0-32 hours) and Cmax values that were established. In addition, comparison of variation in Ciclosporin concentration in whole blood (as determined by specific monoclone RIA) with time after single administration of test preparations with a Ciclosporin dose of 150 mg shows a marked reduction in response variation between all patients receiving the preparation according to claim 1, compared in those in all patients who received the standard formulation.

Similar or equivalent results can be obtained after oral administration of other compositions of the invention, for example as described herein in the examples.

Claims (33)

Pharmaceutical preparation, characterized in that it comprises: a) a cyclosporine as active ingredient, b) a fatty acid saccharide monoester and c) a diluent or carrier, wherein I) component (c) is a solvent for both components (a) and (b), wherein components (a) and (b) each independently have a room temperature solubility in component (c) of at least 10%, or II) component (c) is a solvent for both components (a) and (b) ) and components (a) and (c) are present in the composition in a ratio of 1: 0.5 to 50 parts by weight of [(a) :( c)], or III) component (c) is a solvent for both components (a) and (b) and the preparation is formulated in solid dosage unit form suitable for oral administration, or IV) component (c) comprises a poly (C2.4 alkylene) glycol having an average molecular weight of up to 7000 or a viscosity at 50 ° C of not more than 15000 mPa.s, or a c3.5 alkylene polyol ether or ester, or V) not the preparation, or is substantially non-aqueous, or VI) component (c) comprises a solid polymeric carrier, an organosilicon oxide polymer or paraffinum per- or sub-liguidum and component (a) is present in the preparation in solid solution in (b), Pharmaceutical preparation, characterized in that it comprises: a) a cyclosporin as active ingredient, b) a fatty acid saccharide ester and c) a diluent selected from c1) ethanol, c2) C2-4 alkylene glycols, c3) C3-5 alkylene polyols, c4) poly- (C2-4alkylene) glycols and mixtures thereof, wherein II) components (a) and (c) are present in the composition in a ratio of 1: 0.5 to 50 parts by weight t (a): (c)], or III ) the preparation is formulated in a solid dosage unit form suitable for oral administration, or IV) component (c) comprises a component (c4) with an average molecular weight of at most 7000 or a viscosity at 50 ° C of at most 15,000 mPa.s, or V) the preparation is not, or practically not, aqueous. Preparation according to claim 2, characterized in that component (c) is selected from: c2) 1,2-propylene glycol, c3) glycerol and c4) polyethylene glycols with an average molecular weight of at most 7000 or a viscosity at 50 ° C not exceeding 15,000 mPa.s. Pharmaceutical preparation, characterized in that it comprises: a) a cyclosporine as active ingredient, b) a fatty acid saccharide monoester and c) 1,2-propylene glycol, wherein II) components (a) and (c2) are present in the preparation in a ratio of 1: 0.5 to 50 parts by weight [(a): (c ')], or III) the preparation is formulated in solid dosage unit form, suitable for oral administration, or V) the preparation is not, or substantially is not watery. Pharmaceutical composition, characterized in that it comprises: a) a cyclosporine as active ingredient, b) a fatty acid saccharide ester and c5) a C3-5 alkylene polyol ether or ester. Preparation according to claim 5, characterized in that component (c5) comprises a transesterification product of a natural or hydrogenated vegetable oil and a polyethylene glycol. Preparation according to claim 6, characterized in that component (o5) comprises a transesterification product of a natural or hydrogenated vegetable oil and a polyethylene glycol with a molecular weight of 500-4000. Preparation according to claim 6 or 7, characterized in that component (c5) comprises a transesterification product of a natural or hydrogenated vegetable oil, a polyethylene glycol and glycerol. Preparation according to any one of claims 5-8, characterized in that components (a) and (c5) are present therein in a ratio of 1: 0.5 to 50 parts by weight. Preparation according to any one of claims 1 to 9, characterized in that components (a) and (c) or, in the case of claim 4, (c2), or in the case of claims 5-9, (c5) are contained therein in a ratio of 1: 1 to 10 parts by weight of [(a): (c) / (c) 2 / (c5)]. Preparation according to claim 10, characterized in that the ratio therein is 1: 1.5 to 2.5 parts by weight. Preparation according to any one of claims 1-11, characterized in that components (a) and (b) are present therein in a ratio of 1: 3 to 200 parts by weight [(a) :( b)]. Preparation according to claim 12, characterized in that the ratio therein is 1: 5 to 20 parts by weight. Preparation according to claim 13, characterized in that the ratio therein is 1: 6 to 6.5 parts by weight. Pharmaceutical composition, characterized in that it comprises: (a) a cyclosporin as an active ingredient in solid solution in (b) a fatty acid saccharide ester and (c6) a solid polymeric carrier. Preparation according to claim 15, characterized in that component (c6) comprises a polyvinylpyrrolidone. Preparation according to claim 15 or 16, characterized in that components (a) and (b) are present therein in a ratio of 1: 2 to 20 parts by weight [(a) :( b)]. Preparation according to claim 17, characterized in that the ratio therein is 1: 3 to 8 parts by weight. Preparation according to any one of claims 15-18, characterized in that component (c6) is present therein in an amount of at least 10% by weight based on the total weight of the preparation. Preparation according to claim 19, characterized in that component (c6) is present therein in an amount of 15-50% by weight, based on the total weight of the preparation. Preparation according to any one of claims 15-20, characterized in that it additionally comprises (d) a water-swellable component. Preparation according to claim 21, characterized in that components (d) and (c6) are present therein in a ratio of 1: 0.5 to 4 parts by weight [(d) :( c6)]. A preparation according to any one of claims 1-23 in a dosage unit form, characterized in that it contains 2-200 mg of component (a) per dosage unit. A preparation according to claim 23, characterized in that it contains about 10 or 20 or about 100 mg of component (a) per dosage unit. Pharmaceutical preparation, characterized in that it comprises: a) a cyclosporine as active ingredient, b) a fatty acid saccharide monester and c2) 1,2-propylene glycol, which preparation is in dosage unit form and per dosage unit about 20 to about 100 mg component ( a) contains components (a) and (b) present in the composition in a ratio of 1: 3 to 200 parts by weight [(a): (b)] and components (a) and (c) present in the composition are in a ratio of 1: 0.5 to 50 parts by weight. A preparation according to claim 25, characterized in that components (a) and (b) are present therein in a ratio of 1: 5 to 10 parts by weight and components (a) and (cj are present therein in a ratio of 1: 1.5 to 2.5 parts by weight. 27. A composition according to any one of claims 1 to 26, characterized in that it is in an oral dosage form encapsulated in soft or hard gelatin. A preparation according to any one of claims 1-27, characterized in that it additionally comprises a stabilizer or buffering agent. 29. A composition according to claim 28, characterized in that it is buffered to a pH of 3-8. A preparation according to any one of claims 1-29, characterized in that component (a) is Ciclosporin or [Nva] 2-Ciclosporin. A preparation according to any one of claims 1-30, characterized in that component (b) comprises a water-soluble fatty acid saccharide monoester. The preparation according to claim 31, characterized in that component (b) comprises a C 6-18 fatty acid di- or tri-saccharide ester. The preparation according to claim 32, characterized in that component (b) comprises raffinose or sucrose monolaurate. 34. Pharmaceutical preparation as described in the description and / or the examples. -o-o-o-o-o-o-